Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:29])[N:18]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:13][C@H:12]2[C:30]([NH:32][CH2:33][CH2:34][NH:35][CH2:36][C:37](=[O:39])[NH2:38])=[O:31])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH3:46][O:47][C:48]1[CH:55]=[CH:54][CH:53]=[CH:52][C:49]=1[CH2:50]Cl.CCN(C(C)C)C(C)C>C(#N)C.C(Cl)(Cl)Cl>[CH2:24]([N:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:17]([N:14]1[CH2:15][CH2:16][N:11]([C:9](=[O:10])[N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C@H:12]([C:30]([NH:32][CH2:33][CH2:34][N:35]([CH2:50][C:49]2[CH:52]=[CH:53][CH:54]=[CH:55][C:48]=2[O:47][CH3:46])[CH2:36][C:37](=[O:39])[NH2:38])=[O:31])[CH2:13]1)=[O:29])[CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCN(CCCCC)C(=O)N1CCN(C(=O)N(c2ccccc2)c2cccc(Cl)c2)[C@H](C(=O)NCCNCC(N)=O)C1
Reactant: COc1ccccc1CCl
Solvent: ClC(Cl)Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCN(CCCCC)C(=O)N1CCN(C(=O)N(c2ccccc2)c2cccc(Cl)c2)[C@H](C(=O)NCCN(CC(N)=O)Cc2ccccc2OC)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 23 %

Procedure:
A solution of 74 mg (ca. 0.11 mmole) of 1-(N-(3-chlorophenyl)-N-phenylcarbamoyl)-2-(2-(N-(methylcarboxamido)amino)-N-(methyl)ethylaminocarbonyl)- 4-(N,N-di-n-pentylcarbamoyl)piperazine (from Step E above) in 2 mL of acetonitrile was treated with 72 mg (0.23 mmole) of a 50 wt % solution of 2-methoxybenzyl chloride in chloroform and 60 microliters (0.35 mmole) of DIEA, and the mixture was stirred at room temperature for 24 hours and then at 80° C. for 36 hours. After cooling to room temperature, the mixture was concentrated in vacuo and the residue purified by flash chromatography on 23 g of silica gel eluting with 500 mL of 100:3:0.1 CH2Cl2 :methanol:ammonia water. Impure fractions containing product were resubmitted to the chromatographic conditions given above. The pooled product fractions were then purified by flash chromatography on 23 g of silica gel eluting with 700 mL of 100:2 CH2Cl2 :methanol and then 200 mL of 100:4 CH2Cl2 :methanol to provide 20 mg (23%) of an oil.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:17](O[C:20](=O)[C:12]=12)=O.[C:22](O)(=O)[CH3:23]>C(O)C>[N:11]1[C:12]2[C:13](=[CH:17][CH:22]=[CH:23][CH:20]=2)[CH:14]=[CH:15][C:16]=1[NH:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6]
Reactant: CC(=O)O
Reactant: O=C1OC(=O)c2ncccc21
Reactant: NC(=O)CC[C@H](N)C(=O)O
Solvent: CCO
Product: NC(=O)CC[C@H](Nc1ccc2ccccc2n1)C(=O)O
Yield: 23 %

Procedure:
A stirred suspension of (S)-glutamine (14.6 g, 100 mL) and pyridine-2,3-dicarboxylic anhydride (14.9 g, 100 mmol) in 100 mL of acetic acid is heated at reflux for 1 hour. The resulting solution is allowed to cool. The solid which forms upon cooling is filtered and the solid washed with acetic acid and dried to afford 7.11 g (26%) of crude product. The crude product is slurried in 700 mL of refluxing ethanol, the suspension cooled, and the slurry collected by filtration and dried to afford 6.10 g (23%) of N-quinolinylglutamine, which can be alternatively named as 2-(1,3-dioxo-4-azaisoindol-2-yl)-3-carbamoylpropionic acid, as a white powder. mp 222°-226° C.; 1H NMR (dmso-d6) δ 13.25 (br s, 1 H, COOH), 9.04 (dd, 1 H, J=1.2, 4.9 Hz, pyr), 8.37 (dd, 1 H, J=1.2, 7.8 Hz, pyr), 7.85 (dd, 1 H, J=4.9, 7.8 Hz, pyr), 7.20 (s, 1 H, CONH2), 6.73 (s, 1 H, CONH2), 4.83 (dd, 1 H, J=10.2, 4.8 HZ, CHN), 2.55-1.90 (m, 4 H, CH2CH2); 13C NMR (dmso-d6) 6 1173.22, 170.21, 165.8, 165.7, 155.4, 150.9, 31.7, 128.3, 126.9, 51.5, 31.4, 24.0.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([OH:12])=O.[OH:13][CH:14]1[CH:20]([NH:21][C:22](=[O:29])[C@@H:23]([NH2:28])[CH2:24][CH:25]([CH3:27])[CH3:26])[CH2:19][CH2:18][CH2:17][N:16]([S:30]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[N:34]=2)(=[O:32])=[O:31])[CH2:15]1.[OH:40][CH:41]1C(NC(=O)[C@@H](N)CC(C)C)CCCN(S(C2C=CC=CN=2)(=O)=O)C1>>[CH3:26][CH:25]([CH3:27])[CH2:24][C@H:23]([NH:28][C:10]([C:2]1[O:1][C:5]2[CH:6]=[CH:7][C:8]([O:40][CH3:41])=[CH:9][C:4]=2[CH:3]=1)=[O:12])[C:22](=[O:29])[NH:21][CH:20]1[CH2:19][CH2:18][CH2:17][N:16]([S:30]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[N:34]=2)(=[O:32])=[O:31])[CH2:15][CH:14]1[OH:13]
Reactant: O=C(O)c1cc2ccccc2o1
Reactant: Cc1cccc(S(=O)(=O)N2CCCC(NC(=O)[C@@H](N)CC(C)C)C(O)C2)n1
Reactant: CC(C)C[C@H](N)C(=O)NC1CCCN(S(=O)(=O)c2ccccn2)CC1O
Product: COc1ccc2oc(C(=O)N[C@@H](CC(C)C)C(=O)NC3CCCN(S(=O)(=O)c4cccc(C)n4)CC3O)cc2c1

Procedure:
Following the procedure of Example 28b except substituting 5-methoxybenzofuran-2-carboxylic acid for benzofuran-2-carboxylic acid and (S)-2-amino-4-methyl-pentanoic acid [3-hydroxy-1-(6-methyl-pyridine-2-sulfonyl)-azepan-4-yl]-amide of Example 235c for (S)-2-amino-4-methyl-pentanoic acid [3-hydroxy-1-(pyridine-2-sulfonyl)-azepan-4-yl]-amide of Example 28b the title compound was prepared: MS(EI) 572 (M+).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:25]1[C:26]2[S:39][CH:38]=[CH:37][C:27]=2[N:28](C(OC(C)(C)C)=O)[N:29]=1)=O)(C)(C)C.[CH3:40][Mg]Br.O>O1CCCC1>[C:18]1([C:17]([C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[NH:8][C:9]([C:25]2[C:26]4[S:39][CH:38]=[CH:37][C:27]=4[NH:28][N:29]=2)=[CH:10]3)([OH:24])[CH3:40])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C[Mg]Br
Reactant: CC(C)(C)OC(=O)n1nc(-c2cc3cc(C(=O)c4ccccc4)ccc3n2C(=O)OC(C)(C)C)c2sccc21
Solvent: C1CCOC1
Solvent: O
Product: CC(O)(c1ccccc1)c1ccc2[nH]c(-c3n[nH]c4ccsc34)cc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
To a solution of 5-benzoyl-2-(1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazol-3-yl)-indole-1-carboxylic acid tert-butyl ester [Intermediate (13)] in anhydrous tetrahydrofuran (5 mL) is added methylmagnesium bromide (1M in tetrahydrofuran, 0.8 mL) at −78° C. Stirred under nitrogen for 30 minutes. Added another 0.88 mL of methylmagnesium bromide and let the reaction warm to room temperature slowly. After overnight water/saturated ammonium chloride (2 mL) is added at 0° C. and extracted twice with ethyl acetate (25 mL). The combined ethyl acetate phases are washed with brine and dried over sodium sulfate. The residue is chromatographed on 10 g silica gel, eluting with 30 to 50% ethyl acetate gradient in heptane to afford 1-phenyl-1-[2-(1H-thieno[3,2-c]pyrazol-3-yl)-1H-indol-5-yl]-ethanol (56 mg, 71%, Example 26) as a beige solid; LC/MS: 360 (M+H); 1H NMR [(CD3)2SO)]: δ 13.20 (1H, s), 11.45 (1H, s), 7.73 (1H, d), 7.62 (1H, s), 7.43 (2H, m), 7.25 (6H, m), 6.59 (1H, s), 5.53 (1H, s), 1.86 (3H, s).
Reaction SMILES: [C:1]1([C:13]([OH:15])=[O:14])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([OH:9])=[O:8])[C:2]=1[C:10]([OH:12])=[O:11].S(=O)(=O)(O)O.[N+:21]([O-])([O-:23])=[O:22].[K+]>O>[N+:21]([C:5]1[CH:6]=[C:1]([C:13]([OH:15])=[O:14])[C:2]([C:10]([OH:12])=[O:11])=[C:3]([C:7]([OH:9])=[O:8])[CH:4]=1)([O-:23])=[O:22]
Reactant: O=C(O)c1cccc(C(=O)O)c1C(=O)O
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: O=C(O)c1cc([N+](=O)[O-])cc(C(=O)O)c1C(=O)O
Yield: 50.4 %

Procedure:
To a stirred mixture of 125 g of 1,2,3-benzenetricarboxylic acid and 900 ml of concentrated sulfuric acid at 60°-70° C is added, gradually over a 2 hour period, 312 g of potassium nitrate. The mixture is heated at 135°-140° C for 16 hours, cooled and treated with ice and water. Some solid is separated out and is dissolved in water. The entire aqueous mixture is extracted with ether, the extract is washed with water and dried over magnesium sulfate. The ether is concentrated to a small volume, and petroleum ether is added to precipitate a white solid. The solid is collected and dried to give 76.5 g of 5-nitro-1,2,3-benzenetricarboxylic acid.
Reaction SMILES: Br[C:2]1[S:24][C:5]2[N:6]([CH3:23])[N:7]=[C:8]([C:12]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[O:13])[S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.CN([CH:28]=[O:29])C.[CH2:30](N(CC)CC)[CH3:31]>>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][NH:14][C:12]([C:8]2[S:9](=[O:11])(=[O:10])[C:4]3[CH:3]=[C:2]([C:30]#[C:31][CH2:28][OH:29])[S:24][C:5]=3[N:6]([CH3:23])[N:7]=2)=[O:13])=[CH:17][CH:18]=1
Reactant: CN(C)C=O
Reactant: CCN(CC)CC
Reactant: CN1N=C(C(=O)NCc2ccc(Cl)cc2)S(=O)(=O)c2cc(Br)sc21
Product: CN1N=C(C(=O)NCc2ccc(Cl)cc2)S(=O)(=O)c2cc(C#CCO)sc21
Temperature: 65 °C
Yield: 25 %

Procedure:
A solution containing the 6-bromo-N-(4-chlorobenzyl)-1-methyl-1H-thieno[2,3-e]-[1,3,4]thiadiazine-3-carboxamide 4,4-dioxide (Preparation 57, 0.19 g), DMF (6 mL), and triethylamine (0.8 mL) is degassed by evacuation under house vacuum and filling with nitrogen 3 times. To this solution is added propargyl alcohol (24 μL), palladium(II)chloride bistriphenylphosphine (8 mg), and copper(I)iodide (14 mg). The mixture is warmed to 65° C. After cooling, the reaction mixture is concentrated under a stream of nitrogen and the resulting residue is partitioned between CH2Cl2 and water. The organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated to give a brown oil. The crude product is chromatographed on a Biotage column eluting with 60% ethyl acetate in heptane (200 mL), 80% ethyl acetate in heptane (200 mL), and ethyl acetate (500 mL) followed by purification by radial chromatography eluting with CH2Cl2 to give 40 mg (25%) of the title compound as a pale yellow solid. Physical characteristics: M.p. 98° C. (dec); MS (ESI+) m/z 446 (M+Na)+; HRMS (FAB) m/z 424.0191 (C17H14ClN3O4S2+H).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[S:9][C:8]([S:11][CH3:12])=[N:7][C:6]=2[CH:5]=[CH:4][C:3]=1[OH:13].Cl[C:15]1[CH:20]=[CH:19][N:18]=[C:17]([C:21]([NH:23][CH3:24])=[O:22])[CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1.O>[Cl:1][C:2]1[C:10]2[S:9][C:8]([S:11][CH3:12])=[N:7][C:6]=2[CH:5]=[CH:4][C:3]=1[O:13][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([C:21]([NH:23][CH3:24])=[O:22])[CH:16]=1
Reactant: CNC(=O)c1cc(Cl)ccn1
Reactant: CSc1nc2ccc(O)c(Cl)c2s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CNC(=O)c1cc(Oc2ccc3nc(SC)sc3c2Cl)ccn1
Temperature: 85 °C
Yield: 50.6 %

Procedure:
To the solution of 7-chloro-2-(methylthio)benzo[d]thiazol-6-ol (80 mg, 0.346 mmol, 1.0 eq) in 1 mL of NMP was added 4-chloro-N-methylpicolinamide (88 mg, 0.519 mmol, 1.5 eq) and cesium carbonate (281 mg, 0.865 mmol, 2.5 eq) at room temperature. The reaction mixture was stirred at 85° C. for >48 hours till ca. 75%-80% completion, thereafter the mixture was diluted with water (ca. 50 mL) and aqueous layer extracted with ethyl acetate (ca. 50 mL×3). Combined organic layers were dried over sodium sulfate, filtered and condensed under reduced pressure to give crude product which was purified on ISCO using gradient 0%-100% ethyl acetate-hexane mixture to give 64 mg of product in 50% yield. LC/MS (m/z) [366.0] (MH+)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][CH2:11][CH2:10][C@@H:9]2[C:13]2[CH:14]=[C:15]([C:30](O)=[O:31])[CH:16]=[C:17]3[C:22]=2[O:21][C:20]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:19][C:18]3=[O:29])[CH:5]=[CH:6][CH:7]=1.[CH3:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][CH2:11][CH2:10][C@@H:9]2[C:13]2[CH:14]=[C:15]([C:30]([N:37]3[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]3)=[O:31])[CH:16]=[C:17]3[C:22]=2[O:21][C:20]([N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)=[CH:19][C:18]3=[O:29])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cc([C@H]2CCCN2c2cccc(F)c2)c2oc(N3CCOCC3)cc(=O)c2c1
Reactant: CN1CCNCC1
Product: CN1CCN(C(=O)c2cc([C@H]3CCCN3c3cccc(F)c3)c3oc(N4CCOCC4)cc(=O)c3c2)CC1
Yield: 32.6 %

Procedure:
8-[(2R)-(1-(3-fluorophenyl)pyrrolidin-2-yl)]-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (see Example 1.06 for preparation; 100 mg, 0.23 mmol) was reacted with 1-methylpiperazine (0.076 ml, 0.68 mmol) using a procedure similar to the one described in example 1.00 to afford 8-[(2R)-(1-(3-fluorophenyl)pyrrolidin-2-yl)]-6-(4-methylpiperazine-1-carbonyl)-2-morpholino-4H-chromen-4-one (39 mg, 33%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[F:16][C:17]([F:27])([F:26])[CH:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)[NH2:19]>>[F:27][C:17]([F:16])([F:26])[CH:18]([NH:19][C:8]([C:5]1[CH:4]=[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)[C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1
Reactant: O=C(O)c1cc(OCC2CC2)c(Cl)cn1
Reactant: NC(c1ccccn1)C(F)(F)F
Product: O=C(NC(c1ccccn1)C(F)(F)F)c1cc(OCC2CC2)c(Cl)cn1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-chloro-4-cyclopropylmethoxy-pyridine-2-carboxylic acid and α-(trifluoromethyl)-2-pyridinemethanamine (CAN 503173-14-6) as starting materials. The racemate (96 mg, 83%) was separated into its enantiomers by preparative chiral HPLC (ChiralPak AD, isopropanol/heptane) and the title compound was isolated as colorless oil; LC-MS (UV peak area, m/z) 100%, 386.0882 (MH+). [α]D20=+22.4 (MeOH).
Reaction SMILES: [CH2:1]([C:8]1[N:12]=[C:11]([OH:13])[O:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:14]([N:17]=[C:18]=[O:19])[CH2:15][CH3:16].C(N(CC)CC)C>O1CCOCC1>[CH2:1]([C:8]1[N:12]([C:18](=[O:19])[NH:17][CH2:14][CH2:15][CH3:16])[C:11](=[O:13])[O:10][N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1nc(Cc2ccccc2)no1
Reactant: CCCN=C=O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCCNC(=O)n1c(Cc2ccccc2)noc1=O
Temperature: 0 °C

Procedure:
8.8 parts of 3-benzyl-5-hydroxy-1,2,4-oxadiazole is stirred for 1 hour at room temperature with 4.3 parts of n-propyl isocyanate and 2 parts of triethylamine in 50 parts of dioxane. The reaction mixture is then poured into ice water, and the precipitated solid is suction filtered and recrystallized from alcohol. There is obtained 8.5 parts (65% of theory) of the desired product; m.p.: 74° C.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[C:11]2[CH:12]=[N:13][C:14]3[N:18](CC4OC=CC=4)[N:17]=[CH:16][C:15]=3[C:10]=2[N:9]2[N:25]=[C:26]([CH3:28])[CH:27]=[C:8]2[N:7]=1)[CH2:2][CH2:3][CH3:4].COCCOCCOC.[Se](=O)=O>>[CH2:1]([NH:5][C:6]1[C:11]2[CH:12]=[N:13][C:14]3[NH:18][N:17]=[CH:16][C:15]=3[C:10]=2[N:9]2[N:25]=[C:26]([CH3:28])[CH:27]=[C:8]2[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1nc2cc(C)nn2c2c1cnc1c2cnn1Cc1ccco1
Agent: O=[Se]=O
Solvent: COCCOCCOC
Product: CCCCNc1nc2cc(C)nn2c2c1cnc1[nH]ncc12
Reaction time: 2 h

Procedure:
0.01 mol of N-butyl-8-furfuryl-2-methyl-8H-pyrazolo-[1,5-a]pyrazolo[4', 3':5,6]pyrido[3,4-e]pyrimidin-5-amine is heated in 50 ml of diethyleneglycol dimethyl ether containing 0.01 mol of selenium dioxide a reflux temperature with stirring for two hours. The mixture is filtered hot and evaporated to dryness. N-butyl-2-methyl-8H-pyrazolo[1,5-a]-pyrazolo[4',3':5,6]pyrido[3,4-e]pyrimidin-5-amine remains.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[N:8]=[CH:9][C:10]3[C:15]([C:6]2=[C:5]([C:16]([O:18]C)=[O:17])[CH:4]=[C:3]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:14][CH:13]=[CH:12][CH:11]=3.[OH-].[K+].Cl>C(O)C.O>[O:1]=[C:2]1[N:7]2[N:8]=[CH:9][C:10]3[C:15]([C:6]2=[C:5]([C:16]([OH:18])=[O:17])[CH:4]=[C:3]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:14][CH:13]=[CH:12][CH:11]=3
Reactant: COC(=O)c1cc(-c2ccccc2)c(=O)n2ncc3ccccc3c12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cc(-c2ccccc2)c(=O)n2ncc3ccccc3c12
Temperature: 25 °C

Procedure:
11 g of methyl 4-oxo-3-phenyl-4H-pyrido[2,1-a]phthalazine-1-carboxylate are taken up in 300 ml of ethanol under argon, whereupon a solution of 3.7 g of potassium hydroxide in 30 ml of water is added thereto and the mixture is heated under reflux until the reaction has finished. The reaction mixture is then cooled to room temperature and poured into 2200 ml of water. The mixture is adjusted to pH 7 by adding 1N aqueous hydrochloric acid and impurities are removed by two-fold extraction with 300 ml of methylene chloride each time. The aqueous phase is acidified to pH 1 with 2N aqueous hydrochloric acid and the crystals formed are removed by filtration under suction. After repeated washing with water and drying in vacuo, there is obtained 4-oxo-3-phenyl-4H-pyrido[2,1-a]phthalazine-1-carboxylic acid as yellow crystals of m.p. 236°-237° (dec.).
Reaction SMILES: [ClH:1].Cl.CN[C@H]1CCN(CC(C2CCCCC2O)C2C3C(=CC=CC=3)C=CC=2)C1.[OH:29][C:30]1([CH:36]([C:52]2[C:61]3[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=3)[CH:55]=[CH:54][CH:53]=2)[C:37]([N:39]2[CH2:43][CH2:42][C@H:41]([NH:44][C:45](=O)OC(C)(C)C)[CH2:40]2)=O)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>>[ClH:1].[ClH:1].[CH3:45][NH:44][C@H:41]1[CH2:42][CH2:43][N:39]([CH2:37][CH:36]([C:30]2([OH:29])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]2)[C:52]2[C:61]3[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=3)[CH:55]=[CH:54][CH:53]=2)[CH2:40]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)C(c2cccc3ccccc23)C2(O)CCCCC2)C1
Agent: CN[C@H]1CCN(CC(c2cccc3ccccc23)C2CCCCC2O)C1
Agent: Cl
Product: CN[C@H]1CCN(CC(c2cccc3ccccc23)C2(O)CCCCC2)C1

Procedure:
In an analogous manner to Example 13, step 2, 1-[2-[(3S)-3-(methylamino)pyrrolidin-1-yl-1-(1-naphthyl)ethyl]cyclohexanol dihydrochloride was prepared from tert-butyl {(3S)-1-[(1-hydroxycyclohexyl)(1-naphthyl)acetyl]pyrrolidin-3-yl}carbamate MS (ESI) m/z 353; HRMS: calcd for C23H32N2O+H, 353.25929; found (ESI, [M+H]+), 353.2589.
Reaction SMILES: [OH-:1].[Na+].[OH:3][CH:4]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:5][CH2:6][CH2:7][N:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH3:20])[C:17]([OH:19])=[O:18])[C:9]#[N:10].OO.Cl>O.C(O)C>[OH:3][CH:4]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:5][CH2:6][CH2:7][N:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH3:20])[C:17]([OH:19])=[O:18])[C:9]([NH2:10])=[O:1]
Reactant: [OH-]
Reactant: CCCCCC(O)CCCN(C#N)CCCCCC(C)C(=O)O
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCCCC(O)CCCN(CCCCCC(C)C(=O)O)C(N)=O

Procedure:
To a solution of sodium hydroxide (0.4 g., excess) in water (50 ml.) and ethanol (50 ml.) is added 7-[N-(4-hydroxynonyl)-cyanamido]-2-methylheptanoic acid (1.5 g., 0.005 mole). The clear solution that is obtained is treated with 30% hydrogen peroxide (1.25 ml., excess). After two hours the reaction is poured into water (125 ml.), acidified with 5% hydrochloric acid and extracted with ethyl acetate (3 × 75 ml.). The organic phase is washed with brine, then dried over sodium sulfate. Evaporation of the solvent yields 7-[1-(4-hydroxynonyl)ureido]-2-methyl-heptanoic acid as a viscous oil.
Reaction SMILES: [Cl:1][C:2]1[C:3](C(O)=O)=[N:4][C:5](S(C)(=O)=O)=[N:6][CH:7]=1.[C@H:15]1([NH2:25])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][CH2:16]1.C1(C(N)C2CCCCC2)CCCCC1>CN1CCCC1=O>[Cl:1][C:2]1[CH:7]=[N:6][C:5]([NH:25][C@H:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][CH2:17][CH2:16]2)=[N:4][CH:3]=1
Reactant: N[C@@H]1CCCc2ccccc21
Reactant: CS(=O)(=O)c1ncc(Cl)c(C(=O)O)n1
Agent: NC(C1CCCCC1)C1CCCCC1
Solvent: CN1CCCC1=O
Product: Clc1cnc(N[C@@H]2CCCc3ccccc32)nc1
Yield: 11 %

Procedure:
0.20 g (0.84 mmol) of 5-chloro-2-(methylsulfonyl)pyrimidine-4-carboxylic acid, 0.15 g (1.01 mmol) of (1R)-1,2,3,4-tetrahydronaphthalene-1-amine and 0.33 g (1.69 mmol) of dicyclohexylmethylamine in 1.5 ml of N-methylpyrrolidone are heated in a closed cuvette in the microwave at 150° C. for 30 minutes (Biotage Initiator, http://www.biotage.com/DynPage.aspx?id=22001). The crude mixture obtained in this manner is applied to silica gel and purified by column chromatography using the mobile phase heptane/ethyl acetate. Concentration gives initially 0.024 g of 5-chloro-N-[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]pyrimidine-2-amine (solid) and then 0.08 g of 2-(methylsulfonyl)-N-[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]pyrimidine-5-amine (wax-like, yield 31% at a purity of 95%).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[F:20][C:21]1[CH:22]=[C:23]([CH2:28][C:29](O)=[O:30])[CH:24]=[C:25]([F:27])[CH:26]=1>>[F:20][C:21]1[CH:22]=[C:23]([CH2:28][C:29]([NH:1][N:2]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:19])=[O:30])[CH:24]=[C:25]([F:27])[CH:26]=1
Reactant: Nn1nc(-c2ccc(F)cc2)c2ccccc2c1=O
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Product: O=C(Cc1cc(F)cc(F)c1)Nn1nc(-c2ccc(F)cc2)c2ccccc2c1=O

Procedure:
The product of Example 129A and 2-(3,5-difluorophenyl)acetic acid were treated using a method similar to that described in Example 17C to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.77-11.79 (bs, 1H), 8.40-8.43 (m, 1H), 7.90-8.03 (m, 2H), 7.69-7.74 (m, 1H), 7.63-7.69 (m, 2H), 7.38-7.43 (m, 2H), 7.06-7.21 (m, 3H), 3.77-3.78 (bs, 2H); MS (APCI+) M/Z 410 (M+H)+.
Reaction SMILES: [N:1]([C@@H:4]([C@H:8]([C:16]1[CH:24]=[CH:23][C:19]2[O:20][CH2:21][O:22][C:18]=2[CH:17]=1)[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)[C:5](O)=[O:6])=[N+:2]=[N-:3].[NH2:25][C:26]1[CH:27]=[N:28][CH:29]=[C:30]([F:57])[C:31]=1[CH2:32][CH2:33][C@H:34]1[O:39][CH2:38][C@H:37]([CH2:40][O:41][C:42]([NH:44][CH2:45][C:46]([F:49])([F:48])[F:47])=[O:43])[N:36]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:35]1.O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[N:1]([C@@H:4]([C@H:8]([C:16]1[CH:24]=[CH:23][C:19]2[O:20][CH2:21][O:22][C:18]=2[CH:17]=1)[C:9]1[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=1)[C:5]([NH:25][C:26]1[CH:27]=[N:28][CH:29]=[C:30]([F:57])[C:31]=1[CH2:32][CH2:33][C@H:34]1[O:39][CH2:38][C@@H:37]([CH2:40][O:41][C:42](=[O:43])[NH:44][CH2:45][C:46]([F:49])([F:47])[F:48])[N:36]([C:50]([O:52][C:53]([CH3:55])([CH3:54])[CH3:56])=[O:51])[CH2:35]1)=[O:6])=[N+:2]=[N-:3]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(N)cncc2F)OC[C@@H]1COC(=O)NCC(F)(F)F
Reactant: [N-]=[N+]=N[C@H](C(=O)O)[C@@H](c1ccc(Cl)cc1)c1ccc2c(c1)OCO2
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(F)cncc2NC(=O)[C@@H](N=[N+]=[N-])[C@@H](c2ccc(Cl)cc2)c2ccc3c(c2)OCO3)OC[C@H]1COC(=O)NCC(F)(F)F
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
The product from step 1 (55 mg, 0.16 mmol) and the product from step 4 of Example 89 (76 mg, 0.16 mmol) were dissolved in pyridine (2 mL) and the stirred solution was cooled to −10° C. in an ice/acetone bath. To the cold solution was added POCl3 (0.02 mL, 0.19 mmol). The mixture was stirred at −10° C. for 30 min. The reaction was quenched by the addition of saturated aqueous NaHCO3 solution (2 mL) and the mixture was allowed to warm to ambient temperature. The mixture was diluted with water (mL) and extracted with dichloromethane (3×10 mL). The combined dichloromethane phases were dried (Na2SO4), filtered, and the filtrate solvents were removed in vacuo. The residue was purified on a 12 g silica gel column using a gradient elution of 0-100% EtOAc:hexanes. Fractions containing product were combined and the solvents were removed in vacuo to give the title compound as a gum. (M+H)+=808.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Br:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([O:16][CH3:17])[CH:10]=[CH:9]2.S(=O)(=O)(O)O>C(OC(=O)C)(=O)C>[Br:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12]([N+:1]([O-:4])=[O:2])=[C:11]([O:16][CH3:17])[CH:10]=[CH:9]2
Reactant: COc1ccc2cc(Br)ccc2c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Product: COc1ccc2cc(Br)ccc2c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 81.8 %

Procedure:
An ice-cooled solution of 100% nitric acid (12.0 ml, 0.27 mol) in 95 ml of acetic anhydride was added dropwise to a solution of 6-bromo-2-methoxynaphthalene (61.7 g, 0.26 mol) and 0.25 ml of conc. sulfuric acid in 570 ml of acetic anhydride while maintaining the temperature at +30° to +40° C. The mixture was stirred for an additional 10 min. and filtered. The solid was washed with water and dried to give 60.0 g (73%) of the nitro compound. M.p. 151°-152° C., 1H-NMR (CDCl3): 3.98 (s, 3H, CH3), 7.16-7.93 (m, 5H, ArH).